Appropriate control of angiogenesis offers opportunities for ameliorating a number of diseases. Enhancement of angiogenesis would be beneficial in treating cardiac and peripheral ischemia; inhibition of angiogenesis would be beneficial in treating diabetic retinopathy, macular degeneration and cancer. A deeper understanding of the molecular and cellular mechanisms involved in vascular development and angiogenesis is vital for designing the best approaches to therapy. This project will focus on analyses of the roles of cell adhesion molecules, particularly integrin receptors and extracellular matrix proteins (fibronectin, thrombospondin, von Willebrand factor) in the development and maintenance of the cardiovascular system. There is clear evidence that these proteins play major roles and cooperate with growth with growth factor/receptor pairs. We have developed knockout mice lacking each of the matrix proteins mentioned, as well as knockouts for several integrin subunits (alpha4, alpha5, alphav, beta3, etc.) believed to be involved in cardiovascular development and angiogenesis. Several of these mutant mice display defects in heart or vessel development of varying severity. We will use these and other mice and cells derived from them to investigate the respective roles of these components and the interplay among and other signaling mechanisms (VEGF, angiopoetins, FGF-2, PDGF, TGFbeta). We will concentrate on understanding the roles of integrin receptors including alphav integrins, which are under trials as targets for anti- angiogenesis therapy, as well as other integrins and their extracellular matrix ligands. We will analyze strains of mice lacking various of these components and analyze the effects on endothelial and pericyte functions in vivo and in vitro. We will interact with other Projects under this Program Project in analyzing cardiac angiogenesis, in mapping and characterizing novel genes contributing to cardiac and vascular development, in analyses of roles of adhesion receptors in atherosclerosis and in the development, in analyses of roles of adhesion receptors in atherosclerosis and in the development and exploitation of DNA arrays designed of cardiovascular tissues and cell types. Our approach will combined transgenic and knockout mouse genetics, molecular cell biology and genomic analytical approaches. We will make extensive use of both the Transgenic and Genomics Cores.